The present invention relates to a process of purifying methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, an intermediate in the synthesis of fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (sevoflurane). More specifically, the invention relates to a process for removing dimethyl ether from an intermediate used in a preferred synthesis of sevoflurane. Using the methods of the invention the safety, efficiency, and yield of the sevoflurane synthetic process are improved.
In recent years, fluorinated ethers have been discovered which have useful anesthetic properties. Included among these is sevoflurane ((CF3)2CHOCH2F). Sevoflurane is an advantageous inhalation anesthetic because it provides for rapid onset of anesthesia and rapid recovery. Sevoflurane is administered by the inhalation route to warm-blooded animals in an amount of from about 1% to 5% by volume in admixture with oxygen or a gaseous mixture containing oxygen in an amount sufficient to support respiration.
A preferred process for preparing sevoflurane consists of the three-step process that is depicted in Scheme 1. In the first step, reaction of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) with dimethyl sulfate in the presence of base provides methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether in high yields. Second, the ether can then be treated in a photochemical chlorination procedure to provide chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether. In the third step, the chloromethyl ether from the second step is reacted with a nucleophilic fluoride source, such as a tertiary amine hydrofluoride salt, to displace of the chlorine with fluoride ion and provide sevoflurane. 
U.S. Pat. Nos. 3,683,092 and 3,689,571 disclose the method of the first step of producing methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether by reaction of HFIP with dimethyl sulfate. This reaction provides a high yield of the desired product, together with a small amount of HFIP, which can be removed from the desired product by washing with aqueous sodium hydroxide solution.
The washed product contains dimethyl ether (up to about 2% by weight under certain conditions), which forms as a by-product by reaction of methanol (formed by base catalyzed hydrolysis of dimethyl sulfate) with dimethyl sulfate. In addition, dimethyl ether in the reagent dimethyl sulfate can further contribute to contamination of the desired product.
While dimethyl ether itself is not particularly hazardous (although it is very flammable), by-products formed from contaminating dimethyl ether in subsequent synthetic steps impose problematic handling and purification burdens in the synthesis of sevoflurane. Specifically, dimethyl ether, if present, can be chlorinated in the second synthetic step forming various chlorinated dimethyl ether species that contaminate the desired intermediate, chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether.
One of the chlorinated dimethyl ether compounds which may be produced as a by-product in the second step is bis-chloromethyl ether (ClCH2OCH2Cl). As chlorinated dimethyl ethers are halogenated organics, regulatory concerns often mandate costly hazardous waste disposal procedures. Moreover, contaminating dimethyl ether species interfere with the purification of later process intermediates and in the purification of sevoflurane, itself
Finally, chlorinated dimethyl ethers, if present in the third chemical step of the preferred process, can react to form chlorofluoro ethers. Such chlorofluoro ethers require the burdensome disposal procedures that have been mentioned above for halogenated organics. Chlorofluoro ethers are problematic sevoflurane product contaminants.
What is needed are new processes for removing dimethyl ether from sevoflurane processes that assure high purities of process intermediates and subsequently produced sevoflurane. Processes for dimethyl ether removal are preferably economical and convenient to implement in manufacturing processes.
In one embodiment, the invention relates to a process for purifying methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether. In the process, a composition having methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether and dimethyl ether is passed through an evaporation zone. Dimethyl ether is evaporated by passing a gas stream through the composition, and the gas containing dimethyl ether is removed from the composition. The evaporation zone is heated in certain embodiments of the process. Preferably, the temperature of the evaporation zone is from about 60 to 80xc2x0 C. In preferred embodiments at this evaporation zone temperature, the pressure of the evaporation zone is from about 15 to 25 psig.
In yet another embodiment, the invention relates to a process for preparing fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether. In this process, 1,1,1,3,3,3-hexafluoro-2-propanol and dimethyl sulfate can be reacted to provide a composition containing methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether and dimethyl ether. Methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether can be purified by passing the composition through an evaporation zone, evaporating dimethyl ether by passing a gas stream through the composition, and removing the gas containing dimethyl ether from the composition. The purified methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether can be chlorinated to provide chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether. This chloromethyl ether can then be treated with a nucleophilic fluoride source to obtain fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether.